Hidden receptors in fat cells reveal new sensing mechanism for metabolism

Researchers from the University of Birmingham have uncovered a completely new mechanism by which fat cells (adipocytes) control how they store and release fat.

Published today in Nature Chemical Biology, their study shows that a receptor previously known to respond to dietary fats can also work inside the cell, next to fat storage compartments called lipid droplets.

The results of the study change our understanding of how fat metabolism is regulated and could lead to new strategies in treating obesity, diabetes and other metabolic diseases. The study is a collaboration with scientists at the Universities of Copenhagen, Glasgow and Montréal.

“This discovery could change the way we think about drug development for metabolic diseases, offering more precise ways to regulate fat metabolism,” said Professor Davide Calebiro, Department of Metabolism and Systems Science, University of Birmingham.

Fat cells are specialized cells that store energy in the form of fat. When our body needs energy, fat cells release fatty acids in a process called lipolysis. Lipolysis is a delicate process; too much can lead to excess fat in the blood (a risk factor for diabetes and heart disease), while too little can make it difficult for the body to access stored energy.

Receptors like the one the researchers investigated (known as free fatty acid receptor 4 or FFA4), are part of the large family of G protein-coupled receptors (GPCRs). These receptors are found in cell membranes and play a crucial role in cell signaling. Traditionally, these receptors were thought to only be active on the cell surface, responding to signals from outside the cell.

However, the researchers found that FFA4 receptors are mainly located inside fat cells, on internal membranes near lipid droplets. When fat is broken down, the released fatty acids immediately activate these internal receptors. This triggers a local “brake” on fat breakdown, creating a fast, self-regulating feedback loop at each individual lipid droplet.

This “intracrine” signaling (meaning the cell uses its own internally generated signal) is a completely new concept for metabolite-sensing receptors like FFA4.

Dr. Shannon O’Brien, Research Fellow at the University of Birmingham, said, “We were surprised to find that FFA4 works like a built-in sensor inside fat cells, controlling fat breakdown in real time. This discovery reveals that fat cells have a highly localized way to control fat release, which could be crucial for maintaining healthy metabolism.”

Understanding this mechanism opens up new possibilities for designing innovative therapies that specifically target these intracellular FFA4 receptors. These treatments could help regulate fat storage and release in a more precise way, which could be particularly beneficial for people with metabolic diseases such as type 2 diabetes or obesity.

Davide Calebiro, Professor of Molecular Endocrinology at the University of Birmingham and senior author of the study, said, “This discovery not only describes a completely novel mechanism of ‘intracrine’ signaling, which could be relevant for other metabolically relevant receptors, but could also lead to the development of a new generation of more effective and better tolerated therapies for metabolic diseases.”